Hemophilia is a rare, genetically acquired disorder in which blood does not clot properly due to a lack of clotting proteins (coagulation factors) and/or non-protein blood coagulation compounds (e.g., calcium, phosphate and platelet glycerides). Individuals with the disease do not bleed more intensely, just for longer periods of time. Three types of hemophilia are classified according to the deficient factor. Hemophilia A is the most common and is caused by insufficient levels of factor VIII, whereas hemophilia B and C are less common and are caused by insufficient factor IX and XI levels, respectively. The effects of the disease are often profound: uncontrolled internal bleeding can damage organs and tissues, threatening survival. Currently, no cure for hemophilia exists; however, regular intravenous infusions of the deficient clotting factor can help control the disease. The current standard of care is both inconvenient to the patient and very costly. Therefore, a need exists for additional therapies that target the coagulation cascade, either as a substitute for or in conjunction with clotting factor infusion.
Antithrombin III (AT3, also known as SERPINC1) is a key natural anticoagulant and a genetically defined target. AT3 is expressed in the liver and circulates in the plasma. It inactivates a critical protein, thrombin, which is involved in clotting. While primarily an inhibitor of thrombin, AT3 also inhibits certain activated clotting factors (Xa, IXa, XaI, XIIa, IIa, and VIIa). Thus, an effective inhibitor of AT3 would prevent the ability of AT3 to inactivate thrombin, resulting in increased active thrombin and clot formation, thereby providing an additional hemophilia therapeutic.
Double-stranded RNA (dsRNA) agents that are believed to be processed by the Dicer enzyme of the RNA interference (RNAi) pathway—leading such agents to be termed “Dicer substrate siRNA” (“DsiRNA”) agents—have been described as effective inhibitors of target gene expression in mammalian cells (Rossi et al., U.S. Pat. No. 8,084,599 and U.S. Patent Application No. 2005/0277610). Additional modified structures of DsiRNA agents were previously described (Rossi et al., U.S. Patent Application No. 2007/0265220). Effective extended forms of Dicer substrates have also been more recently described (Brown, U.S. Pat. Nos. 8,349,809 and 8,513,207).